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Small Vessel Disease

Perpetrator or Predictor of Stroke in Patients With Atrial Fibrillation?
Originally published 2021;52:100–102

In this edition of Stroke, Du et al1 report findings from a prospective multicenter inception cohort study (CROMIS-2 [Clinical Relevance of Microbleeds in Stroke]) indicating that patients with history of a stroke or transient ischemic attack and known atrial fibrillation (AF) on oral anticoagulation (either vitamin K antagonist or a direct acting oral anticoagulant) have a higher risk for recurrent stroke if they also have magnetic resonance imaging evidence of small vessel disease (SVD). All enrollees underwent MRI by protocol to reveal what have been proposed as the imaging markers for cerebral SVD: chronic lacunes, expanded perivascular spaces, microhemorrhages, and white matter hyperintensity.2,3 The investigators followed patients by mail or phone for 2 years and detected recurrent stroke in 53 out of 1419 (3.6%) patients, a rate of 1.62 per 100 patient-years. The 53 patients with recurrence were different from the 1366 without recurrent stroke in the usual ways (older, more often female, diabetic, higher CHA2DS2-VASc score) but also in having the imaging stigmata of SVD. The significance of statistical associations of SVD stigmata survived adjustments with summary CHA2DS2-VASc scores and with the individual components of CHA2DS2-VASc noted above (eg, age, female sex, etc).

See related article, p 91

A final analysis undertaken by the authors yielded an unexpected result. Using the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) ischemic stroke classification system,4 the authors categorized the 53 recurrent ischemic strokes clinically by mechanism, and found only 3 of the 53 (5.7%) ischemic strokes were classified due to the small vessel (or lacunar) mechanism. In the discussion, the authors advocate for addressing the higher rate of stroke as though it were a downstream effect of SVD.

Among the report’s strengths is its methods, featuring follow-up of a prospectively enrolled cohort. Trained experts within the authorship interpreted each study scan. Intra- and interobserver agreement were excellent.1 Limitations include lack of information about the occurrence and frequency of intracerebral hemorrhage, adequacy of risk factor control, presence of other pathologies related to AF itself (paroxysmal versus permanent), or associated with AF (left atrial size, heart failure), and whether any patients were on antiplatelet as well as anticoagulation or had to interrupt their anticoagulation for procedures or trauma.

The main contribution of this study is making the point that patients with AF with evidence of SVD by MRI had higher incidence of stroke recurrence compared with those without evidence of SVD. These findings from a prospective inception cohort mark them as truly predictive. Yet, how do we reconcile this with the low rate of recurrence of small vessel stroke compared with other stroke types? Was SVD a predictor or an actual perpetrator of future ischemic strokes?

The authors mention that SVD-related recurrent stroke may have been underestimated because of the preexistence of AF influencing the clinical categorization. This is an intrinsic limitation of TOAST, which does not allow the identification of multiple etiologies. Perhaps if a different categorization system was used, such as the ASCOD (for A: atherosclerosis; S: small-vessel disease; C: cardiac pathology; O: other causes) scheme, the relationships would have changed.5

However, if the authors’ intuition is in fact correct and SVD is the perpetrator for recurrent stroke, then one must wonder about the management of SVD during the study period. The current study did not report additional antithrombotic therapy on top of anticoagulation.

Multiple reports have demonstrated that the combination of anticoagulation and antiplatelet therapy has been associated with increased bleeding complications without added benefit. Those reports include, as pointed out by the authors, ORBIT-AF trial (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation),6 ARISTOTLE trial (Apaxaban versus Warfarin in Patients with Atrial Fibrillation),7 and ROCKET-AF trial (Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation)8 as well as the recently published GARFIELD-FA (Global Anticoagulant Registry in the Field-Atrial Fibrillation), which included over 24 000 unselected patients with AF.9 Even without anticoagulation, prolonged dual antithrombotic therapy using 2 antiplatelet agents has not been shown to be more effective than single antiplatelet therapy for secondary stroke prevention in patients with lacunar strokes. Indeed, the SPS3 trial (Secondary Prevention of Small Subcortical Strokes) examined adding clopidogrel to aspirin versus aspirin alone in preventing recurrent lacunar stroke and found that enhanced antiplatelet action was, if anything, dangerous because of increased risk of intracerebral hemorrhage on the dual antiplatelet program.10

The association of imaging features of SVD with higher rate of future ischemic stroke implies, but does not prove, directionality of effect. Until proven otherwise, we advocate for addressing causes of SVD to reduce rate of ischemic stroke recurrence regardless of mechanism. Perhaps the more important component of stroke prevention in SVD is risk factor management. The current study did not detect any difference in the frequency of hypertension diagnosis between the patients who had a recurrent stroke and those who did not. The study did not examine how well the blood pressure was controlled during the study period. Therefore, it is plausible that patients with poorly controlled hypertension had more advanced SVD on imaging and suffered recurrent strokes and that tight blood pressure control would have lowered the rate of SVD-related stroke recurrence. Based on the SPS3 trial, in patients who suffered a lacunar stroke, aiming for systolic blood pressure goal <130 mm Hg was associated with reduction of recurrent lacunar stroke compared with a less aggressive goal <150 mm Hg, although that association did not reach statistical significance (hazard ratio, 0.81 [95% CI, 0.64–1.03]; P=0.08).10 Supporting this notion is a recent meta-analysis of 4 trials including patients with stroke, with diabetes, and those 70 years or older, which demonstrated the lower rate of SVD progression in the subjects who used antihypertensive medications.11 Moreover, the rate of intracerebral hemorrhage was significantly lower in the more aggressive arm of SPS3 (hazard ratio, 0.37 [95% CI, 0.15–0.95]; P=0.03).12

A true missing link here is the role of atherosclerosis. The available data did not include complete examination for atherosclerotic disease. Only carotid disease is commented on. It was found to be more prevalent in patients with recurrent stroke (32% versus 18%; hazard ratio, 2.24 [95% CI, 1.26–3.99]), although carotid disease did not affect the association between recurrent ischemic stroke and SVD. Other relevant vascular beds, particularly the intracranial circulation, were not reported but one may assume that they were affected by atherosclerosis to some degree. This is important because SVD correlates with large vessel disease. In the population-based, prospective 3C-Dijon (Three-City Dijon) study, carotid plaque detected by ultrasound was associated with the presence of lacunar strokes (odds ratio, 1.60 [95% CI, 1.09–2.35]) and with white matter hyperintensity (odds ratio, 1.32 [95% CI, 1.04–1.67]). Markers of carotid stiffness were also associated with SVD.13 Another study showed the association of intracranial calcification, a marker of atherosclerosis with white matter hyperintensities, lacunes, and cerebral microbleeds.14 Thus, SVD and large vessel atherosclerotic disease (both cervical and intracranial) are markers for each other. Based on that, one may assume that, in the current study, the patients who suffered recurrent stroke and had significantly higher SVD burden also had higher atherosclerotic burden leading to recurrent strokes that were misclassified by TOAST.

In conclusion, the current analysis of CROMIS-2 study is valuable in pointing out the multifaceted nature of stroke cause. The presence of one clear cause (in this case AF) should not distract us from addressing all the other possible causes. The study also highlights the importance of SVD-related imaging markers as predictors of recurrent stroke. The low rate of recurrent small vessel stroke suggests that SVD is a predictor of ischemic stroke of any of the mechanism categories. It is possible that this low number of clinical small vessel strokes was because of faulty classification of at least some of the recurrent strokes as non-SVD related when in fact they were. As the mechanistic explanation of recurrent stroke remains unclear, it follows that the best regimen for stroke prevention is also unclear. One safe bet is to focus on vascular risk factors.


The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

For Disclosures, see page 102.

Correspondence to: David C. Anderson, MD, 2022 Summit Ave, St Paul, MN 55105. Email


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